title: Increased ERK signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z α1-antitrypsin.
abstract: Overexpression of Z α1-antitrypsin is known to induce polymer formation, prime the cells for endoplasmic reticulum stress and initiate nuclear factor kappa B (NF-κB) signalling. However, whether endogenous expression in primary bronchial epithelial cells has similar consequences remains unclear. Moreover, the mechanism of NF-κB activation has not yet been elucidated. Here, we report excessive NF-κB signalling in resting primary bronchial epithelial cells from ZZ patients compared with wild-type (MM) controls, and this appears to be mediated by mitogen-activated protein/extracellular signal-regulated kinase, EGF receptor and ADAM17 activity. Moreover, we show that rather than being a response to protein polymers, NF-κB signalling in airway-derived cells represents a loss of anti-inflammatory signalling by M α1-antitrypsin. Treatment of ZZ primary bronchial epithelial cells with purified plasma M α1-antitrypsin attenuates this inflammatory response, opening up new therapeutic options to modulate airway inflammation in the lung.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors.forename: Emily F A
authors.initials: EF
authors.lastname: van 't Wout
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Dickens
authors.forename: Annemarie
authors.initials: A
authors.lastname: van Schadewijk
authors.forename: Imran
authors.initials: I
authors.lastname: Haq
authors.forename: Hang Fai
authors.initials: HF
authors.lastname: Kwok
authors.forename: Adriana
authors.initials: A
authors.lastname: Ordóñez
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: Jan
authors.initials: J
authors.lastname: Stolk
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Marciniak
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000473:pathology; D020935:MAP Kinase Signaling System; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D061251:Primary Cell Culture; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D000515:alpha 1-Antitrypsin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D000515:alpha 1-Antitrypsin; C512478:EGFR protein, human; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human